DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-55 are pending and being examined.
Claim Objections
2. Claims 5-41 and 49-55 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, claims 5-41 and 49-55 have not been further treated on the merits.
3. Claim 4 is objected to because of the following informalities: Claim 4 appears to be missing the word “the” in front of “single dose”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 42-48 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 42, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 42 recites the broad recitation of antibody concentrations ranging from 100 mg/ml to 200 mg/mL, and the claim also recites the antibody concentration is “preferably 150 mg/mL” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 42 recites a pharmaceutical composition comprising an antibody and is directed to a product invention, however, the claim recites the phrase: “and whereupon following administration of the composition to a subject in need thereof, at least…and the subject having a baseline serum HBsAg level less than 3000 IU/mL” which is considered a method step or process invention, rendering the claim unclear as to whether a product or a process is being claimed. Clarification is required. Dependent claims are rejected for encompassing the rejected limitations of claim 42. For the sake of compact prosecution and prior art comparison, Examiner will interpret the limitation as an intended use of the composition.
5. Claims 3 and 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 3 recites the limitation "the single dose". There is insufficient antecedent basis for this limitation in the claim. Claim 4 is rejected for depending on claim 3 and encompassing the rejected limitation.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claim 48 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 48 depends from claim 43. Claim 43 is limited to an amount of antibody “up to 3,000 mg” as the highest amount. Claim 48 recites the amount of antibody is “up to about 3,000 mg” which encompasses values around 3,000 mg, including values exceeding 3,000 mg that are outside the scope of claim 43. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
7. Claim(s) 42-48 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application 2022/0380441, Pang et al, claiming priority to August 29, 2019.
The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Pang claims:
36. A pharmaceutical composition comprising an antibody, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:91 and the light chain amino acid sequence of SEQ ID NO:93 (which are 100% identical to instant SEQ ID NOs:91 and 93), wherein the pharmaceutical composition comprises the antibody at a concentration ranging from 100 mg/mL to 200 mg/mL, such as 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, or 200 mg/mL, preferably 150 mg/mL.
37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises up to 6 mg, up to 18 mg, up to 75 mg, up to 90 mg, up to 300 mg, up to 900 mg, or up to 3000 mg of the antibody.
38. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 75 mg of the antibody.
39. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 90 mg of the antibody.
40. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 300 mg of the antibody.
41. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 900 mg of the antibody.
42. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 3,000 mg of the antibody
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
8. Claims 1, 2, 4 are rejected under 35 U.S.C. 103 as being obvious over US Patent Application 2022/0380441, Pang et al, claiming priority to August 29, 2019; in view of WO2020/132091, Corti, claiming priority to December 2018; Galun et al (Hepatology, 2002, 35:673-679); and Kang et al (Protein Cell, 2018, 9:130-134).
The applied reference has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Pang teaches a method of treating HBV infection in a subject comprising administering to the subject a single dose of pharmaceutical composition comprising an antibody comprising heavy and light chain SEQ ID NOs:91 and 93 (HBC34-v35-MLNS-GAALIE) ([187]; [272]; claims 1-12, 17-33) that are 100% identical to instant SEQ ID Nos:91 and 93;
wherein the dose comprises at least 6mg or 75 mg ([336]; [343]; [632]; Table 9; claims 3 and 5);
wherein the subject has a baseline HBsAg level <1000 IU/mL ([329-330]; [568-569]; [639]; [695]; Embodiment 71; claim 28);
wherein 56 days following administration of the single dose, the method results in a greater than 2-fold reduction in serum HBsAg compared to baseline after the single dose, a range which encompasses changes of at least 1.0 log10 IU/ml ([341]; claim 32; Embodiments 73 and 106; claim 32).
Pang explains the infection process of HBV and recognizes that T cell exhaustion occurs due to high HBsAg levels, resulting in chronic infections instead of viral clearance ([3]):
The three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg shape a complex transmembrane fold at the endoplasmic reticulum, and form disulfide-linked homo- and heterodimers. During budding at an intracellular membrane, a short linear domain in the cytosolic preS region interacts with binding sites on the capsid surface. The virions are subsequently secreted into the blood. In addition, the surface proteins can bud in the absence of capsids and form subviral particles (SVPs) which are also secreted in 3-4 log excess over virions. High level of HBsAg can exhaust HBsAg-specific T-cell response, and is proposed as an important factor for viral immunotolerance in patients with chronic hepatitis B (CHB)
Pang does not teach the method results in a reduction of serum HBsAg persisting for 1 or more, or 14 or more days following administration of the single dose, or HBsAg is reduced within 8 days of administration.
Corti teaches a method of treating hepatitis B virus (HBV) infection in a subject, the method comprising administering to the subject a single dose of pharmaceutical composition comprising an antibody HBC34-V35, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:91 (HBC34-V35 heavy chain variant HBC34-V35-MLNSGAALIE) and the light chain amino acid sequence of SEQ ID NO:93 (HBC34-V35) (Table 1 on p. 30-31; p. 66-67, claims 34, 36), which are 100% identical to instant SEQ ID NOs:91 and 93, respectively (see sequence alignments below).
Corti further teaches the single dose does not exceed a dose selected from 500 mg, 250 mg, 100 mg, and 50 mg, which encompasses doses of at least 6mg and at least 75 mg (p. 103, line 29 to p. 104, line 5).
Corti further teaches the antibody is capable of reducing the serum concentration of HBsAg in a treated mammal for about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more days following a single administration of the binding protein (p. 48, lines 3-11).
Corti demonstrates treating a mouse model of HBV infection with the HBC34-V35 antibody at a dose of 15 mg/kg (i.p, 2x/week) that successfully reduced the level of serum HBsAg concentration after treatment compared to baseline levels by at least 1.0 log10 IU/ml (10-fold), and serum HBsAg concentration was reduced compared to baseline levels for up to about 20 days (Example 5, Figure 6).
Corti explains the infection process of HBV and recognizes that T cell exhaustion occurs due to high HBsAg levels, resulting in chronic infections instead of viral clearance (p. 1, line 26 to p. 2, line 7):
The three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg shape a complex transmembrane fold at the endoplasmic reticulum, and form disulfide-linked homo- and heterodimers. During budding at an intracellular membrane, a short linear domain in the cytosolic preS region interacts with binding sites on the capsid surface. The virions are subsequently secreted into the blood. In addition, the surface proteins can bud in the absence of capsids and form subviral particles (SVPs) which are also secreted in 3-4 log excess over virions. High level of HBsAg can exhaust HBsAg-specific T-cell response, and is proposed as an important factor for viral immunotolerance in patients with chronic hepatitis B (CHB)
Galun also teaches the need to manage chronic HBV infection (p. 677, Discussion). Galun teaches clinically treating HBV by administering antibodies against HBsAg. Galun teaches administering various doses of antibody including a single dose ranging from 0.26 mg to 40 mg in Phase 1A (Table 1), or administering 4 doses ranging from 10 mg to 80 mg in Phase 1B (Table 2). Galun demonstrates that after administration of a single dose of 39 mg or 30 mg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction persisted at least the 5 days measured (Figure 1). Galun demonstrates that during and after administration of four doses of 10 mg or 20 mg, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction below baseline level persisted at least 14 days (Figures 2 and 3). Galun concludes that administration of monoclonal antibodies to chronic HBV-infected patients significantly reduced HBV-DNA levels and HBsAg levels indicating viral neutralization (p. 678, col. 1, last paragraph).
Kang teaches preclinically treating HBV infection in mice and cynomolgus monkeys by administering an antibody that binds to HBsAg, wherein monkeys received 10 mg/kg or 20 mg/kg (Figure 1; p. 132, col. 1). The total mg of antibody administered would be about 100 mg – 160 mg for the average weight of a cynomolgus monkey ranging 5 kg – 8 kg, which is greater than 6 mg and greater than 75 mg. Treatment resulted in significant serum HBsAg reduction within 48 hours of administration of antibody (Figure 1H). Kang teaches the need to administer a high dose of antibody for chronic viral infections because of the requirement to effectively eradicate the circulating virus (p. 132, col. 2, middle paragraph). Kang teaches another solution to reduce HBsAg levels is to enhance serum persistence of the antibody to increase HBsAg targeting and reduction (p. 132, col. 2, middle paragraph; p. 133, col. 2, first two paragraphs).
Treatment result in serum HBsAg level reduction by at least 1.0 log10 IU/ml with the reduction of serum HBsAg persisting 1 or more days or 14 or more days (claims 1 and 2):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of Pang to result in serum HBsAg level reduction by at least 1.0 log10 IU/ml with the reduction of serum HBsAg persisting 1 or more days or 14 or more days. One would have been motivated to because: (1) all of Pang, Corti, Galun, and Kang teach the need to treat chronic HBV infection by administering antibody against HBsAg, in order to reduce HBsAg levels below baseline for a prolonged period, reduce immune exhaustion to HBV antigens, restore HBV-specific T-cell response, and develop long-lasting protective immunity; (2) Pang, Corti, Galun, and Kang teach administering HBsAg antibodies for HBV treatment at doses greater than 6 mg or greater than 75 mg; (3) Kang teaches the importance of administering a high dose of antibody to treat chronic HBV infection in order to reduce HBsAg levels and effectively eradicate the circulating virus; and (4) Corti teaches the antibody is capable of reducing the serum concentration of HBsAg in a treated mammal for about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more days following a single administration of the antibody.
One of ordinary skill in the art would have a reasonable expectation of success given: (1) Corti demonstrates the HBV antibody successfully reduced the level of serum HBsAg concentration after treatment compared to baseline levels by at least 1.0 log10 IU/ml, and serum HBsAg concentration was reduced compared to baseline levels for up to about 20 days even at a dose of antibody lower than 6 mg; (2) Galun demonstrates that after administration of a single dose of 39 mg or 30 mg HBsAg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction in levels persisted at least 5 days; (3) Galun demonstrates that after administration of four doses of 10 mg or 20 mg of HBsAg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction below baseline level persisted at least 14 days; and (4) Kang successfully demonstrated administering HBsAg antibody at a dose greater than 6 mg and greater than 75 mg resulted in significant serum HBsAg reduction within 48 hours of administration of antibody.
Serum HBsAg reduced compared to baseline by at least 1.0 log10 IU/ml within 8 days of administration (claim 4):
Further, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for this method to result in serum HBsAg reduced compared to baseline by at least 1.0 log10 IU/ml within 8 days of administration. One would have been motivated to, and have a reasonable expectation of success to, because: (1) all of Pang, Corti, Galun, and Kang teach treating chronic HBV infection with an antibody against HBsAg for the purpose of reducing HBsAg levels below baseline in order to reduce immune exhaustion to HBV antigens, restore HBV-specific T-cell response, and develop long-lasting protective immunity; (2) Corti, Galun, and Kang demonstrate successfully and significantly reducing HBsAg levels compared to baseline in less than 1 day.
9. Claim 3 is rejected under 35 U.S.C. 103 as being obvious over US Patent Application 2022/0380441, Pang et al, claiming priority to August 29, 2019; in view of WO2020/132091, Corti, claiming priority to December 2018; and Kang et al (Protein Cell, 2018, 9:130-134).
The applied reference has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Pang teaches as set forth above. Pang further teaches enhancing serum half-life of the antibody by mutating the Fc region, where such known mutations include Fc mutations M252Y/S254T/T256E (“YTE”) or the Fc mutation M428L/ N434S/ G236A/ A330L/ I332E (“MLNS-GAALIE”) that is comprised in heavy chain SEQ ID NO:91 ([29]; [149]; [163-168]; [261-268]).
Pang does not teach the method results in 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days following administration.
Corti teaches a method of treating hepatitis B virus (HBV) infection in a subject, the method comprising administering to the subject a single dose of pharmaceutical composition comprising an antibody HBC34-V35, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:91 (HBC34-V35 heavy chain variant HBC34-V35-MLNS-GAALIE) and the light chain amino acid sequence of SEQ ID NO:93 (HBC34-V35) (Table 1 on p. 30-31; p. 66-67, claims 34, 36), which are 100% identical to instant SEQ ID NOs:91 and 93, respectively (see sequence alignments below).
Corti explains the infection process of HBV and recognizes that T cell exhaustion occurs due to high HBsAg levels, resulting in chronic infections instead of viral clearance (p. 1, line 26 to p. 2, line 7):
The three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg shape a complex transmembrane fold at the endoplasmic reticulum, and form disulfide-linked homo- and heterodimers. During budding at an intracellular membrane, a short linear domain in the cytosolic preS region interacts with binding sites on the capsid surface. The virions are subsequently secreted into the blood. In addition, the surface proteins can bud in the absence of capsids and form subviral particles (SVPs) which are also secreted in 3-4 log excess over virions. High level of HBsAg can exhaust HBsAg-specific T-cell response, and is proposed as an important factor for viral immunotolerance in patients with chronic hepatitis B (CHB).
Corti further teaches enhancing serum half-life of the antibody by mutating the Fc region, where such known mutations include Fc mutations M252Y/S254T/T256E (“YTE”) or the Fc mutation M428L/ N434S/ G236A/ A330L/ I332E (“MLNS-GAALIE”) that is comprised in heavy chain SEQ ID NO:91 (p. 65-66; Example 2; claims 18-36).
Kang teaches as set forth above. Kang further teaches the need for enhanced serum persistence of the HBsAg antibody in order to increase HBsAg targeting and reduction during chronic infection. Kang teaches accomplishing this by mutating the Fc region of the antibody to extend serum half-life (p. 130; p. 133). Kang demonstrates engineering the Fc region of their HBsAg antibody to comprise Fc mutations M252Y/S254T/T256E (“YTE”) and demonstrates this modification successfully and significantly extends antibody half-life after a single dose compared to wild-type antibody lacking the Fc modification (Figure 1E-G), and significantly reduces HBsAg levels compared to wild-type antibody lacking the Fc modification (Figure 1H).
Achieve at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days after administration of antibody (claim 3(b)):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of Pang to achieve at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days after administration of antibody. One of ordinary skill in the art would have been motivated to, and have a reasonable expectation of success to, given: (1) cited references teach the need to reduce HBsAg levels for a sustained time in order to reduce immune cell exhaustion in chronic HBV infection; (2) Pang teaches achieving >2-fold reduction in serum HBsAg 56 days after administration of antibody; (3) Pang, Corti and Kang teach a solution to increase reduction of serum HBsAg is to extend the serum half-life of the HBsAg antibody by modifying the Fc region; (4) Pang and Corti teach their antibody comprising SEQ ID NO:91 comprises a half-life extending Fc modification; and (4) Kang demonstrated that an Fc modification of an HBsAg antibody successfully resulted in significantly extending antibody half-life after a single dose compared to wild-type antibody lacking the Fc modification, and significantly reduced HBsAg levels compared to wild-type antibody lacking the Fc modification. The cited references provide both the motivation and means for achieving at least 1000 ng/ml of Pang’s Fc-modified HBsAg antibody remaining unbound to serum HBsAg for at least 14 days after administration, with a reasonable expectation of success.
10. Claim(s) 42-48 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020/132091, Corti, published June 2020, claiming priority to December 2018; in view of Shire, S.J., Liu, J., Friess, W., Jörg, S. and Mahler, H.C., 2010. High-concentration antibody formulations (pp. 349-381). John Wiley & Sons, Inc: Hoboken, NJ, USA.
Corti teaches a pharmaceutical composition comprising an antibody, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:91 and the light chain amino acid sequence of SEQ ID NO:93 (p. 99-103; 66-67, claims 34, 36, 67, and 68), which are 100% identical to instant SEQ ID NOs:91 and 93, respectively (see sequence alignments below). Corti further teaches a single dose of antibody can comprise 500 mg, 250 mg, 100 mg, or 50 mg (p. 103, line 29 to p. 104, line 5).
Corti further teaches utilizing the antibody for detection of HBsAg protein or diagnosis of HBV infection (p. 39-40; p. 93-95; claims 69, 73, 81), or for neutralization assays (p. 43-44).
Corti does not teach the composition comprises the antibody specifically at a concentration range of 100 mg/ml to 200 mg/ml, or that the composition comprises up to 6, 75, 90, 300, 900 or 3,000 mg of antibody.
Shire teaches known methods of formulating therapeutic monoclonal antibodies at high concentrations. Shire teaches (section 15.1.3): “A significant number of antibodies are currently in development or clinical testing with concentrations as high as 100–150 mg/mL by many pharmaceutical companies, and a summary of the currently approved high-concentration antibody products is given in Table 15.1” where Table 15.1 demonstrates commercially available antibodies packaged at concentrations of 100 mg/ml and 125 mg/ml. Shire teaches the advantages of packaging antibodies at high concentrations include (section 15.6): improving patient convenience and providing competitiveness in the market, and high-concentration formulations require less storage space and may reduce overall shipping costs, owing to the minimized storage volume of the concentrated bulk and drug products.
Antibody concentration range of 100 mg/ml to 200 mg/ml (claim 42):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed formulate the antibody pharmaceutical composition of Corti in a range of high concentration of 100 mg/ml to 200 mg/ml. One would have been motivated to and have a reasonable expectation of success to because: (1) Corti teaches formulating the therapeutic monoclonal antibody in a pharmaceutical composition and high doses include amounts of 500 mg, 250 mg, or 100 mg; (2) Shire teaches the advantage of formulating therapeutic antibodies at high concentrations for a high dose including improving patient convenience and providing competitiveness in the market, and high-concentration formulations require less storage space and may reduce overall shipping costs, owing to the minimized storage volume of the concentrated bulk and drug products; and (3) Shire teaches the known success of formulating therapeutic monoclonal antibodies at high concentrations including commercially available antibodies formulated at 100 mg/ml or 150 mg/ml.
Antibody amounts ranging from about 6 mg to about 3,000 mg (claims 43-48):
Additionally, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed formulate the antibody pharmaceutical composition of Corti to comprise any amount of antibody, including any amounts ranging from about 6 mg to about 3,000 mg. One would have been motivated to and have a reasonable expectation of success to because: (1) Corti teaches the antibody can be used for multiple purposes, including treatment of HBV, HBsAg protein detection, HBV diagnosis, and HBV neutralization assays; and (2) Shire demonstrates packaging formulations of antibody at various amounts is known and commercially accomplished. Given the known need to utilize the antibody of Corti for various methods that inherently require various amounts of antibody, given the known methods for commercially packaging antibody at various amounts; it is well within the level of the ordinary skilled artisan to produce an antibody composition of Corti that comprises any amount of antibody, including within a range of about 6 mg to about 3000 mg, for applications in various methods with a reasonable expectation of success.
11. Claim(s) 1, 2, and 4 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020/132091, Corti, claiming priority to December 2018; in view of Galun et al (Hepatology, 2002, 35:673-679); ClinicalTrials.gov NCT03575208, Record History version 168, published December 2019; and Kang et al (Protein Cell, 2018, 9:130-134).
Corti teaches a method of treating hepatitis B virus (HBV) infection in a subject, the method comprising administering to the subject a single dose of pharmaceutical composition comprising an antibody HBC34-V35, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:91 (HBC34-V35 heavy chain variant HBC34-V35-MLNSGAALIE) and the light chain amino acid sequence of SEQ ID NO:93 (HBC34-V35) (Table 1 on p. 30-31; p. 66-67, claims 34, 36), which are 100% identical to instant SEQ ID NOs:91 and 93, respectively (see sequence alignments below).
Corti further teaches the single dose does not exceed a dose selected from 500 mg, 250 mg, 100 mg, and 50 mg, which encompasses doses of at least 6mg and at least 75 mg (p. 103, line 29 to p. 104, line 5).
Corti further teaches the antibody is capable of reducing the serum concentration of HBsAg in a treated mammal for about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more days following a single administration of the binding protein (p. 48, lines 3-11).
Corti demonstrates treating a mouse model of HBV infection with the HBC34-V35 antibody at a dose of 15 mg/kg (i.p, 2x/week) that successfully reduced the level of serum HBsAg concentration after treatment compared to baseline levels by at least 1.0 log10 IU/ml (10-fold), and serum HBsAg concentration was reduced compared to baseline levels for up to about 20 days (Example 5, Figure 6).
Corti explains the infection process of HBV and recognizes that T cell exhaustion occurs due to high HBsAg levels, resulting in chronic infections instead of viral clearance (p. 1, line 26 to p. 2, line 7):
The three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg shape a complex transmembrane fold at the endoplasmic reticulum, and form disulfide-linked homo- and heterodimers. During budding at an intracellular membrane, a short linear domain in the cytosolic preS region interacts with binding sites on the capsid surface. The virions are subsequently secreted into the blood. In addition, the surface proteins can bud in the absence of capsids and form subviral particles (SVPs) which are also secreted in 3-4 log excess over virions. High level of HBsAg can exhaust HBsAg-specific T-cell response, and is proposed as an important factor for viral immunotolerance in patients with chronic hepatitis B (CHB)
Corti does not teach specifically administering at least 6 mg of antibody as a single dose and following that single dose, the serum HBsAg level was reduced by at least 1.0 log10 IU/ml and the reduction of serum HBsAg persisted 1 or more days (claim 1).
Corti does not teach specifically administering at least 75mg of antibody as a single dose and following that single dose, the serum HBsAg level was reduced by at least 1.0 log10 IU/ml and the reduction of serum HBsAg persisted for at least 14 or more days (claim 2).
Corti does not teach the methods of claims 1 and 2 result in serum HBsAg reduced compared to baseline by at least 1.0 log10 IU/ml within 8 days of administration of the single dose (claim 4).
Galun also teaches the need to manage chronic HBV infection (p. 677, Discussion). Galun teaches clinically treating HBV by administering antibodies against HBsAg. Galun teaches administering various doses of antibody including a single dose ranging from 0.26 mg to 40 mg in Phase 1A (Table 1), or administering 4 doses ranging from 10 mg to 80 mg in Phase 1B (Table 2). Galun demonstrates that after administration of a single dose of 39 mg or 30 mg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction persisted at least the 5 days measured (Figure 1). Galun demonstrates that during and after administration of four doses of 10 mg or 20 mg, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction below baseline level persisted at least 14 days (Figures 2 and 3). Galun concludes that administration of monoclonal antibodies to chronic HBV-infected patients significantly reduced HBV-DNA levels and HBsAg levels indicating viral neutralization (p. 678, col. 1, last paragraph).
NCT03575208 teaches clinically treating chronic HBV-infected patients by administering large doses (20,000 U/L) of an antibody that binds to HBsAg, in order to remove HBsAg from the blood, reduce immune exhaustion to HBV antigens, and to restore adaptive and innate immune response to HBV. NCT03575208 teaches this will lead to HBsAg clearance, restoration of HBV-specific T-cell response, and development of long-lasting protective immunity (p. 21-22, Objectives and Detailed Description; p. 24-25, Outcome Measures). NCT03575208 teaches treating patients having a known HBsAg serum level of <1,500 IU/mL at baseline (Inclusion Criteria, p. 26).
Kang teaches preclinically treating HBV infection in mice and cynomolgus monkeys by administering an antibody that binds to HBsAg, wherein monkeys received 10 mg/kg or 20 mg/kg (Figure 1; p. 132, col. 1). The total mg of antibody administered would be about 100 mg – 160 mg for the average weight of a cynomolgus monkey ranging 5 kg – 8 kg, which is greater than 6 mg and greater than 75 mg. Treatment resulted in significant serum HBsAg reduction within 48 hours of administration of antibody (Figure 1H). Kang teaches the need to administer a high dose of antibody for chronic viral infections because of the requirement to effectively eradicate the circulating virus (p. 132, col. 2, middle paragraph). Kang teaches another solution to reduce HBsAg levels is to enhance serum persistence of the antibody to increase HBsAg targeting and reduction (p. 132, col. 2, middle paragraph; p. 133, col. 2, first two paragraphs).
Administering a single dose of at least 6 mg or at least 75 mg of the HBsAg antibody and result in serum HBsAg level reduction by at least 1.0 log10 IU/ml with the reduction of serum HBsAg persisting 1 or more days or 14 or more days (claims 1 and 2):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for Corti to treat HBV infection in a subject by administering a single dose of at least 6 mg or at least 75 mg of the HBsAg antibody and result in serum HBsAg level reduction by at least 1.0 log10 IU/ml with the reduction of serum HBsAg persisting 1 or more days or 14 or more days. One would have been motivated to because: (1) all of Corti, Galun, NCT03575208, and Kang teach the need to treat chronic HBV infection by administering antibody against HBsAg, in order to reduce HBsAg levels below baseline for a prolonged period, reduce immune exhaustion to HBV antigens, restore HBV-specific T-cell response, and develop long-lasting protective immunity; (2) Corti, Galun, and Kang teach administering HBsAg antibodies for HBV treatment at doses greater than 6 mg or greater than 75 mg; (3) NCT03575208 and Kang teach the importance of administering a high dose of antibody to treat chronic HBV infection in order to reduce HBsAg levels and effectively eradicate the circulating virus; and (4) Corti teaches their antibody is capable of reducing the serum concentration of HBsAg in a treated mammal for about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more days following a single administration of the antibody.
One of ordinary skill in the art would have a reasonable expectation of success given: (1) Corti demonstrates their HBV antibody successfully reduced the level of serum HBsAg concentration after treatment compared to baseline levels by at least 1.0 log10 IU/ml (10-fold), and serum HBsAg concentration was reduced compared to baseline levels for up to about 20 days even at a dose of anitbody lower than 6 mg; (2) Galun demonstrates that after administration of a single dose of 39 mg or 30 mg HBsAg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction in levels persisted at least 5 days; (3) Galun demonstrates that after administration of four doses of 10 mg or 20 mg of HBsAg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction below baseline level persisted at least 14 days; and (4) Kang successfully demonstrated administering HBsAg antibody at a dose greater than 6 mg and greater than 75 mg resulted in significant serum HBsAg reduction within 48 hours of administration of antibody.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case: (1) Corti, Galun, NCT03575208, and Kang teach the need to treat chronic HBV infection by administering antibody against HBsAg, in order to reduce HBsAg levels below baseline for a prolonged period, reduce immune exhaustion to HBV antigens, restore HBV-specific T-cell response, and develop long-lasting protective immunity; (2) Corti, Galun, NCT03575208, and Kang teach and/or demonstrate the solution is to administer an HBsAg antibody at a high enough dose to significantly reduce HBsAg levels compared to baseline, and for a prolonged period; and (3) Corti, Galun, NCT03575208, and Kang teach and/or demonstrate administering various levels of HbsAg antibody less than 6 mg, greater than 6 mg, and greater than 75 mg that all successfully and significantly reduced HBsAg levels compared to baseline and for prolonged period of at least 1, 5, or 14 days. Thus, given the recognized need, solution, and demonstrated success by the cited prior art, one of skill in the art could have pursued treating HBV infection in a subject by administering a single dose of at least 6 mg or at least 75 mg of the HBsAg antibody of Corti, and result in serum HBsAg level reduction by at least 1.0 log10 IU/ml with the reduction of serum HBsAg persisting 1 or more days or 14 or more days, with a reasonable expectation of success.
Serum HBsAg reduced compared to baseline by at least 1.0 log10 IU/ml within 8 days of administration (claim 4):
Further, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for this method to result in serum HBsAg reduced compared to baseline by at least 1.0 log10 IU/ml within 8 days of administration. One would have been motivated to, and have a reasonable expectation of success to, because: (1) all of Corti, Galun, NCT03575208, and Kang teach treating chronic HBV infection with an antibody against HBsAg for the purpose of reducing HBsAg levels below baseline in order to reduce immune exhaustion to HBV antigens, restore HBV-specific T-cell response, and develop long-lasting protective immunity; (2) Corti, Galun, and Kang demonstrate successfully and significantly reducing HBsAg levels compared to baseline in less than 1 day.
12. Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over WO2020/132091, Corti, claiming priority to December 2018; in view of Galun et al (Hepatology, 2002, 35:673-679); ClinicalTrials.gov NCT03575208, Record History version 168, published December 2019; and Kang et al (Protein Cell, 2018, 9:130-134).
Corti teaches a method of treating hepatitis B virus (HBV) infection in a subject, the method comprising administering to the subject a single dose of pharmaceutical composition comprising an antibody HBC34-V35, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO:91 (HBC34-V35 heavy chain variant HBC34-V35-MLNS-GAALIE) and the light chain amino acid sequence of SEQ ID NO:93 (HBC34-V35) (Table 1 on p. 30-31; p. 66-67, claims 34, 36), which are 100% identical to instant SEQ ID NOs:91 and 93, respectively (see sequence alignments below).
Corti explains the infection process of HBV and recognizes that T cell exhaustion occurs due to high HBsAg levels, resulting in chronic infections instead of viral clearance (p. 1, line 26 to p. 2, line 7):
The three HBV envelope proteins S-HBsAg, M-HBsAg, and L-HBsAg shape a complex transmembrane fold at the endoplasmic reticulum, and form disulfide-linked homo- and heterodimers. During budding at an intracellular membrane, a short linear domain in the cytosolic preS region interacts with binding sites on the capsid surface. The virions are subsequently secreted into the blood. In addition, the surface proteins can bud in the absence of capsids and form subviral particles (SVPs) which are also secreted in 3-4 log excess over virions. High level of HBsAg can exhaust HBsAg-specific T-cell response, and is proposed as an important factor for viral immunotolerance in patients with chronic hepatitis B (CHB).
Corti further teaches enhancing serum half-life of the antibody by mutating the Fc region, where such known mutations include Fc mutations M252Y/S254T/T256E (“YTE”) or the Fc mutation M428L/ N434S/ G236A/ A330L/ I332E (“MLNS-GAALIE”) that is comprised in heavy chain SEQ ID NO:91 (p. 65-66; Example 2; claims 18-36).
Corti does not teach the method results in at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days following administration and the subject treated has a baseline serum HBsAg level <3000 IU/ml.
Galun, NCT03575208, and Kang teach as set forth above.
Galun further demonstrates treating patients having baseline (pretreatment) HBsAg levels ranging from 0.02 to 85 µg/ml (Table 1 and 2).
NCT03575208 further teaches including patients for HBsAg antibody treatment who have baseline serum HBsAg levels <1500 IU/ml (Inclusion Criteria, p. 26).
As stated above, Kang teaches the need for enhanced serum persistence of the HBsAg antibody in order to increase HBsAg targeting and reduction during chronic infection. Kang teaches accomplishing this by mutating the Fc region of the antibody to extend serum half-life (p. 130; p. 133). Kang demonstrates engineering the Fc region of their HBsAg antibody to comprise Fc mutations M252Y/S254T/T256E (“YTE”) and demonstrates this modification successfully and significantly extends antibody half-life after a single dose compared to wild-type antibody lacking the Fc modification (Figure 1E-G), and significantly reduces HBsAg levels compared to wild-type antibody lacking the Fc modification (Figure 1H).
Achieve at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days after administration of antibody (claim 3(b)):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of Corti to achieve at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days after administration of antibody. One of ordinary skill in the art would have been motivated to, and have a reasonable expectation of success to, given: (1) cited references teach the need to reduce HBsAg levels for a sustained time in order to reduce immune cell exhaustion in chronic HBV infection; (2) Corti, NCT03575208 and Kang teach one solution is to administer a high dose of antibody; (3) Corti and Kang teach another solution is to extend the serum half-life of the HBsAg antibody by modifying the Fc region; (4) Corti teaches their antibody comprising SEQ ID NO:91 comprises a half-life extending Fc modification; and (4) Kang demonstrated that an Fc modification of an HBsAg antibody successfully resulted in significantly extending antibody half-life after a single dose compared to wild-type antibody lacking the Fc modification, and significantly reduced HBsAg levels compared to wild-type antibody lacking the Fc modification. The cited references provide both the motivation and means for achieving at least 1000 ng/ml of Corti’s Fc-modified HBsAg antibody remaining unbound to serum HBsAg for at least 14 days after administration, with a reasonable expectation of success.
Treat patients having baseline serum HBsAg level <3000 IU/ml (claim 3(c)):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of Corti to treat patients having baseline serum HBsAg level <3000 IU/ml. One of ordinary skill in the art would have been motivated to, and have a reasonable expectation of success to, given: (1) all the cited references teach the need to treat HBV infected patients with an HBsAg antibody and demonstrate a reasonable expectation of success to; (2) Galun demonstrates successfully treating patients having a wide range of baseline HBsAg levels and reducing their HBsAg levels after antibody administration; and (3) NCT03575208 further teaches including patients for HBsAg antibody treatment who have baseline serum HBsAg levels <1500 IU/ml.
Instant SEQ ID NO:91 aligned with Corti SEQ ID NO:91:
RESULT 1
BHY20222
ID BHY20222 standard; protein; 449 AA.
XX
AC BHY20222;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-HBsAg antibody heavy chain, SEQ 91.
XX
KW HBsAg; Hepatitis B surface antigen; antibody; antibody production;
KW antibody therapy; antiinflammatory; antimicrobial-gen.; diagnostic test;
KW gastrointestinal-gen.; heavy chain; hepatitis b virus infection;
KW hepatitis d virus infection; hepatotropic; immune stimulation;
KW immuno-diagnosis; immunoassay; immunotherapy; prophylactic to disease;
KW protein detection; protein production; recombinant protein; therapeutic;
KW virucide.
XX
OS Unidentified.
XX
CC PN WO2020132091-A2.
XX
CC PD 25-JUN-2020.
XX
CC PF 18-DEC-2019; 2019WO-US067216.
XX
PR 19-DEC-2018; 2018US-0782274P.
PR 11-JUN-2019; 2019US-0860085P.
XX
CC PA (HUMA-) HUMABS BIOMED SA.
XX
CC PI Corti D;
XX
DR WPI; 2020-571820/059.
XX
CC PT Isolated antibody, or an antigen binding fragment used in pharmaceutical
CC PT composition of kit for manufacturing medicament for treating,
CC PT attenuating, or diagnosing hepatitis B infection, comprises heavy and
CC PT light chain variable region.
XX
CC PS Claim 34; SEQ ID NO 91; 229pp; English.
XX
CC The present invention relates to a novel isolated antibody, or its
CC antigen binding fragment, useful in a pharmaceutical composition for
CC manufacturing a medicament for treating, preventing, attenuating, or
CC diagnosing hepatitis B infection. The invention further provides: (1) a
CC fusion protein, comprising an extracellular component comprising the
CC antigen binding fragment, a transmembrane domain, and an intracellular
CC component comprising an effector domain or a functional variant or its
CC portion, and optionally comprising a signaling domain from a co-
CC stimulatory protein or a functional variant or its portion; (2) an
CC isolated polynucleotide comprising a nucleotide sequence that encodes the
CC antibody, the antigen binding fragment, or the fusion protein; (3) a
CC vector comprising the polynucleotide; (4) a host cell comprising a
CC heterologous polynucleotide; (5) a pharmaceutical composition comprising
CC the antibody or its antigen binding fragment, the fusion protein, the
CC polynucleotide, the vector, the host cell, or any of their combination;
CC (6) a kit comprising the antibody or its antigen binding fragment, the
CC fusion protein, the polynucleotide, the vector, the host cell, the
CC pharmaceutical composition or any of their combination; (7) a method for
CC producing the antibody or its antigen binding fragment, or the fusion
CC protein; (8) a method of treating, preventing, and/or attenuating a
CC hepatitis B and/or hepatitis D infection in a subject; (9) a method for
CC in vitro diagnosis of a hepatitis B and/or a hepatitis D infection; and
CC (10) a method for detecting the presence or absence of an epitope in a
CC correct conformation in an anti-hepatitis-B and/or an anti-hepatitis-D
CC vaccine.
XX
SQ Sequence 449 AA;
Query Match 100.0%; Score 2393; Length 449;
Best Local Similarity 100.0%;
Matches 449; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
Qy 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSSA120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSSA120
Qy 121 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG180
Qy 181 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLAGP240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLAGP240
Qy 241 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS300
Qy 301 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDEL360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDEL360
Qy 361 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ420
Qy 421 QGNVFSCSVLHEALHSHYTQKSLSLSPGK 449
|||||||||||||||||||||||||||||
Db 421 QGNVFSCSVLHEALHSHYTQKSLSLSPGK 449
Instant SEQ ID NO:93 aligned with Corti SEQ ID NO:93:
RESULT 1
BHY20224
ID BHY20224 standard; protein; 212 AA.
XX
AC BHY20224;
XX
DT 20-AUG-2020 (first entry)
XX
DE Anti-HBsAg antibody light chain, SEQ 93.
XX
KW HBsAg; Hepatitis B surface antigen; antibody; antibody production;
KW antibody therapy; antiinflammatory; antimicrobial-gen.; diagnostic test;
KW gastrointestinal-gen.; hepatitis b virus infection;
KW hepatitis d virus infection; hepatotropic; immune stimulation;
KW immuno-diagnosis; immunoassay; immunotherapy; light chain;
KW prophylactic to disease; protein detection; protein production;
KW recombinant protein; therapeutic; virucide.
XX
OS Unidentified.
XX
CC PN WO2020132091-A2.
XX
CC PD 25-JUN-2020.
XX
CC PF 18-DEC-2019; 2019WO-US067216.
XX
PR 19-DEC-2018; 2018US-0782274P.
PR 11-JUN-2019; 2019US-0860085P.
XX
CC PA (HUMA-) HUMABS BIOMED SA.
XX
CC PI Corti D;
XX
DR WPI; 2020-571820/059.
XX
CC PT Isolated antibody, or an antigen binding fragment used in pharmaceutical
CC PT composition of kit for manufacturing medicament for treating,
CC PT attenuating, or diagnosing hepatitis B infection, comprises heavy and
CC PT light chain variable region.
XX
CC PS Claim 36; SEQ ID NO 93; 229pp; English.
XX
CC The present invention relates to a novel isolated antibody, or its
CC antigen binding fragment, useful in a pharmaceutical composition for
CC manufacturing a medicament for treating, preventing, attenuating, or
CC diagnosing hepatitis B infection. The invention further provides: (1) a
CC fusion protein, comprising an extracellular component comprising the
CC antigen binding fragment, a transmembrane domain, and an intracellular
CC component comprising an effector domain or a functional variant or its
CC portion, and optionally comprising a signaling domain from a co-
CC stimulatory protein or a functional variant or its portion; (2) an
CC isolated polynucleotide comprising a nucleotide sequence that encodes the
CC antibody, the antigen binding fragment, or the fusion protein; (3) a
CC vector comprising the polynucleotide; (4) a host cell comprising a
CC heterologous polynucleotide; (5) a pharmaceutical composition comprising
CC the antibody or its antigen binding fragment, the fusion protein, the
CC polynucleotide, the vector, the host cell, or any of their combination;
CC (6) a kit comprising the antibody or its antigen binding fragment, the
CC fusion protein, the polynucleotide, the vector, the host cell, the
CC pharmaceutical composition or any of their combination; (7) a method for
CC producing the antibody or its antigen binding fragment, or the fusion
CC protein; (8) a method of treating, preventing, and/or attenuating a
CC hepatitis B and/or hepatitis D infection in a subject; (9) a method for
CC in vitro diagnosis of a hepatitis B and/or a hepatitis D infection; and
CC (10) a method for detecting the presence or absence of an epitope in a
CC correct conformation in an anti-hepatitis-B and/or an anti-hepatitis-D
CC vaccine.
XX
SQ Sequence 212 AA;
Query Match 100.0%; Score 1110; Length 212;
Best Local Similarity 100.0%;
Matches 212; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRPSGIPER 60
Qy 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVLGQPKAAPSVTLFPP120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVLGQPKAAPSVTLFPP120
Qy 121 SSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSL180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSL180
Qy 181 TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 212
||||||||||||||||||||||||||||||||
Db 181 TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 212
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
13. Claims 1-4 and 42-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 4, 10-12, 17-33, 36-43, 48 of copending Application No. 17/637,605 in view of WO2020/132091, Corti, published June 2020, claiming priority to December 2018; Galun et al (Hepatology, 2002, 35:673-679); and Kang et al (Protein Cell, 2018, 9:130-134).
The copending application claims a method of treating HBV infection in a subject comprising administering a single dose of pharmaceutical composition comprising an antibody comprising heavy and light chain SEQ ID NOs:91 and 93 that are 100% identical to instant SEQ ID NOs:91 and 93;
wherein the single dose comprises antibody in the range of 2 to 18 mg/kg of subject weight;
wherein the single dose comprises antibody at a concentration of 100 mg/ml to 200 mg/ml;
wherein the pharmaceutical composition comprises 150 mg/ml antibody;
wherein the subject weighs from 40 kg to 125 kg [which encompasses administering a dose of antibody in a range of 80 mg to 2,250 mg for doses 2 to 18 mg/kg that encompass doses at least 6 mg or at least 75 mg];
wherein the subject has chronic HBV infection;
wherein the subject has a baseline serum HBsAg concentration of <1000 IU/ml; and
wherein 56 days after administration of the single dose, the subject has greater than 2-fold reduction in serum HBsAg as compared to their baseline level.
The copending application additionally claims a pharmaceutical composition comprising an antibody comprising heavy and light chain SEQ ID NOs:91 and 93, wherein the antibody is present from 100 mg/ml to 200 mg/ml;
wherein the antibody is present from up to 6mg to up to 3000 mg;
wherein the composition comprises about 75, 90, 300, 900 or about 3000 mg of antibody.
The copending application does not claim the method results in a reduction of serum HBsAg form baseline by at least 1.0 log10 IU/ml, and persisting for 1 or more, or 14 or more days following administration of the single dose, or is reduced within 8 days of administration.
The copending application does not claim the method of treatment results in at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days following administration.
Corti, Galun, and Kang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of the copending application to result in serum HBsAg level reduction compared to baseline by at least 1.0 log10 IU/ml with the reduction of serum HBsAg persisting 1 or more days or 14 or more days. One would have been motivated to because: (1) Corti, Galun, and Kang teach the need to treat chronic HBV infection by administering antibody against HBsAg, in order to reduce HBsAg levels below baseline for a prolonged period, reduce immune exhaustion to HBV antigens, restore HBV-specific T-cell response, and develop long-lasting protective immunity; (2) the copending application claims, and Corti, Galun, and Kang teach administering HBsAg antibodies for HBV treatment at doses greater than 6 mg or greater than 75 mg; (3) Kang teaches the importance of administering a high dose of antibody to treat chronic HBV infection in order to reduce HBsAg levels and effectively eradicate the circulating virus; and (4) Corti teaches the antibody is capable of reducing the serum concentration of HBsAg in a treated mammal for about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more days following a single administration of the antibody.
One of ordinary skill in the art would have a reasonable expectation of success given: (1) Corti demonstrates the HBV antibody successfully reduced the level of serum HBsAg concentration after treatment compared to baseline levels by at least 1.0 log10 IU/ml, and serum HBsAg concentration was reduced compared to baseline levels for up to about 20 days even at a dose of anitbody lower than 6 mg; (2) Galun demonstrates that after administration of a single dose of 39 mg or 30 mg HBsAg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction in levels persisted at least 5 days; (3) Galun demonstrates that after administration of four doses of 10 mg or 20 mg of HBsAg antibody, HbsAg levels were reduced quickly and by at least 10-fold from baseline within 1 day, and the reduction below baseline level persisted at least 14 days; and (4) Kang successfully demonstrated administering HBsAg antibody at a dose greater than 6 mg and greater than 75 mg resulted in significant serum HBsAg reduction within 48 hours of administration of antibody.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the claimed method of the copending application to achieve at least 1000 ng/ml of antibody remaining unbound to serum HBsAg for at least 14 days after administration of antibody. One of ordinary skill in the art would have been motivated to, and have a reasonable expectation of success to, given: (1) the copending application claims treating chronic HBV infection and reducing serum HbsAg by a greater than 2-fold reduction by 56 days after administration; (2) Corti and Kang also teach reducing HBsAg levels for a sustained time in order to reduce immune cell exhaustion in chronic HBV infection; (3) Corti and Kang teach a solution to reducing serum HBsAg is to extend the serum half-life of the HBsAg antibody by modifying the Fc region; (4) Corti teaches the antibody of the copending application comprising SEQ ID NO:91 comprises a half-life extending Fc modification; and (5) Kang demonstrated that an Fc modification of an HBsAg antibody successfully resulted in significantly extending antibody half-life after a single dose compared to wild-type antibody lacking the Fc modification, and significantly reduced HBsAg levels compared to wild-type antibody lacking the Fc modification. The copending application claims the antibody results in an extended time of reducing HBsAg levels by at least 56 days, and the cited references provide both the motivation and means for achieving at least 1000 ng/ml of the copending application’s Fc-modified HBsAg antibody remaining unbound to serum HBsAg for at least 14 days after administration, with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
14. Conclusion: No claim is allowed.
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/Laura B Goddard/Primary Examiner, Art Unit 1642